[HTML][HTML] ER-associated ubiquitin ligase HRD1 programs liver metabolism by targeting multiple metabolic enzymes

J Wei, Y Yuan, L Chen, Y Xu, Y Zhang, Y Wang… - Nature …, 2018 - nature.com
J Wei, Y Yuan, L Chen, Y Xu, Y Zhang, Y Wang, Y Yang, CB Peek, L Diebold, Y Yang, B Gao…
Nature communications, 2018nature.com
The HMG-CoA reductase degradation protein 1 (HRD1) has been identified as a key
enzyme for endoplasmic reticulum-associated degradation of misfolded proteins, but its
organ-specific physiological functions remain largely undefined. Here we show that mice
with HRD1 deletion specifically in the liver display increased energy expenditure and are
resistant to HFD-induced obesity and liver steatosis and insulin resistance. Proteomic
analysis identifies a HRD1 interactome, a large portion of which includes metabolic …
Abstract
The HMG-CoA reductase degradation protein 1 (HRD1) has been identified as a key enzyme for endoplasmic reticulum-associated degradation of misfolded proteins, but its organ-specific physiological functions remain largely undefined. Here we show that mice with HRD1 deletion specifically in the liver display increased energy expenditure and are resistant to HFD-induced obesity and liver steatosis and insulin resistance. Proteomic analysis identifies a HRD1 interactome, a large portion of which includes metabolic regulators. Loss of HRD1 results in elevated ENTPD5, CPT2, RMND1, and HSD17B4 protein levels and a consequent hyperactivation of both AMPK and AKT pathways. Genome-wide mRNA sequencing revealed that HRD1-deficiency reprograms liver metabolic gene expression profiles, including suppressing genes involved in glycogenesis and lipogenesis and upregulating genes involved in glycolysis and fatty acid oxidation. We propose HRD1 as a liver metabolic regulator and a potential drug target for obesity, fatty liver disease, and insulin resistance associated with the metabolic syndrome.
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